Recent data, generated as the result of a decade long effort by the Program PI to develop endothelial progenitor cell based therapeutics, provides evidence for the safety and efficacy of autologous progenitor cells for treatment of myocardial and limb ischemia. Specifically two recent human clinical trials have both yielded evidence that autologous human CD34+ cells improve outcome in patients with chronic, refractory ischemia: patients with intractable angina had significant reductions in chest pain and improved exercise tolerance, while patients with critical limb ischemia had reduced amputation rates. While we acknowledge that the final proof of progenitor cell based therapies in phase III studies is forthcoming, it is our belief that the available evidence for bioactivity and potential therapeutic utility of cell based therapy is substantial enough to justify efforts to augment their efficacy by exploiting our knowledge about their biology and further exploring mechanisms that may enhance their safety and therapeutic utility. The overarching goal of this PPG is to advance the therapeutic use of endothelial progenitor cells for the treatment of cardiovascular diseases. This objective will be achieved in the Program by four individual Projects that investigate certain mechanisms of progenitor cell fate, function and dysfunction, and explore novel, nanomaterial based methods to enhance their therapeutic application and by taking advantage of strategically designed Cores that will support each Project. Project 1: Enhancing Progenitor Cell Function using Bioactive Peptide Amphiphiles (Douglas W. Losordo, M.D. and Samuel Stupp Ph.D., Co-I) Project 2: Role of PAI-1 in Cardiovascular Repair and Fibrosis (Douglas E. Vaughan, M.D., PI) Project 3: Characterization of mitochondrial defects in EPCs in diabetes and aging (Hossein Ardehali, M.D., Ph.D., PI) Project 4: Epigenetic modulation of Endothelial Progenitor Cells for Cardiomyogenesis (Raj Kishore, Ph.D., PI) Core A: Small Animal Surgery and Histology (Tsutomu Kume, Ph.D., PI) Core B: Advanced Molecular Imaging (Tom Meade, Ph.D., PI) Core C: FACS Analysis and Cell Sorting (Harris Perlman, Ph.D., PI) Core D; Administrative Core (Douglas Losordo, M.D., PI) PROJECT 1: Peptide Amphiphiles to Augment Progenitor Cell Therapies (Losordo, Douglas W.)